CLINICAL SCIENCE

Discontinuation of Initial Antiretroviral Therapy in Clinical Practice: Moving Toward Individualized Therapy Antonio Di Biagio, MD,* Alessandro Cozzi-Lepri, PhD,† Roberta Prinapori, MD,* Gioacchino Angarano, MD,‡ Andrea Gori, MD,§ Tiziana Quirino, MD,k Andrea De Luca, MD,¶ Andrea Costantini, MD,# Cristina Mussini, MD,** Giuliano Rizzardini, MD,†† Antonella Castagna, MD,‡‡ Andrea Antinori, MD,§§ and Antonella d’Arminio Monforte, MD,kk for the ICONA Foundation Study Group

Background: Study aim was to estimate the rate and identify predictors of discontinuation of first combination antiretroviral therapy (cART) in recent years.

Methods: Patients who initiated first cART between January 2008 and October 2014 were included. Discontinuation was defined as stop of at least 1 drug of the regimen, regardless of the reason. All causes of discontinuation were evaluated and 3 main endpoints were considered: toxicity, intolerance, and simplification. Predictors of discontinuation were examined separately for all 3 endpoints. Kaplan–Meier analysis was used for the outcome discontinuation

Received for publication June 4, 2015; accepted August 31, 2015. From the *Infectious Diseases Unit, IRCCS AOU S. Martino-IST, National Institute for Cancer Research, Genoa, Italy; †Department of Infection and Population Health, Division of Population Health, UCL Medical School, Royal Free Campus, London, United Kingdom; ‡Department of Biomedical Science and Human Oncology, University of Bari, Bari, Italy; §Clinic of Infectious Diseases, San Gerardo Hospital, University of Milano-Bicocca, Monza, Italy; kInfectious Diseases Unit, Busto Arsizio Hospital, Busto Arsizio (VA), Italy; ¶Infectious Diseases Unit, Siena University Hospital, Siena, Italy; #Department of Health Sciences, University of Ancona, Ancona, Italy; **Infectious Diseases Clinic, Policlinico of Modena, University of Modena and Reggio Emilia, Modena, Italy; ††Infectious Diseases Unit, Sacco Hospital, Milan, Italy; ‡‡Infectious Diseases Unit, Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy; §§National Institute for Infectious Diseases IRCCS L. Spallanzani, Rome, Italy; and kkClinic of Infectious and Tropical Diseases, Department of Health Sciences, S Paolo Hospital, University of Milan, Milan, Italy. Presented in part in poster form at the HIV and Drug Therapy in November 2014 in Glasgow, United Kingdom. The authors have no funding or conflicts of interest to disclose. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.jaids.com). A.D.B., R.P., A.C.-L., A.d.M. conceived of and designed the study; A.C.-L. performed statistical analyses. All authors contributed to the interpretation of the data. A.D.B. and R.P. drafted the manuscript. All authors reviewed the manuscript critically for important intellectual content and approved final version. R.P. and A.D.B. contributed equally to this study. The ICONA Foundation Study Group is listed in Appendix 1. ICONA Foundation is sponsored by unrestricted educational grants from AbbVie, BMS, Gilead, Jannsen, MSD, ViiV, Italy. Correspondence to: Antonio Di Biagio, MD, or Roberta Prinapori, MD, Infectious Diseases Unit, IRCCS A.U.O San Martino-IST, University of Genoa (DISSAL), Largo R. Benzi 10, Genoa 16132, Italy (e-mail: [email protected]). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

of $1 drug regardless of the reason. Cox regression analysis was used to identify factors associated with treatment discontinuation because of the 3 reasons considered.

Results: A total of 4052 patients were included. Main reason for stopping at least 1 drug were simplification (29%), intolerance (21%), toxicity (19%), other causes (18%), failure (8%), planned discontinuation (4%), and nonadherence (2%). In a multivariable Cox model, predictors of discontinuation for simplification were heterosexual transmission (P = 0.007), being immigrant (P = 0.017), higher nadir lymphocyte T CD4+ cell (P = 0.011), and higher lymphocyte T CD8+ cell count (P = 0.025); for discontinuation due to intolerance: the use of statins (P = 0.029), higher blood glucose levels (P = 0.050). About toxicity: higher blood glucose levels (P = 0.010) and the use of zidovudine/lamivudine as backbone (P = 0.044). Conclusions: In the late cART era, the main reason for stopping the initial regimen is simplification. This scenario reflects the changes in recommendations aimed to enhance adherence and quality of life, and minimize drug toxicity. Key Words: antiretroviral therapy, HIV-1, discontinuation, resumption treatment, single-tablet regimen, first-line therapy (J Acquir Immune Defic Syndr 2016;71:263–271)

INTRODUCTION The expanded use of combination antiretroviral therapy (cART) since 1996 has resulted in a marked and sustained decrease in AIDS-related morbidity and mortality,1–3 with a range of benefits to HIV-infected patients, such as increased survival, improved immune status, and decreased of opportunistic infections.4–6 Current regimen options are more effective, better tolerated, less toxic, than regimens used in the early years of the cART era7; therefore, optimization of initial antiretroviral therapy in terms of both virological efficacy and tolerability is essential because long-term toxicity and persistency are fundamental features in the choice of first-line cART. Rates and reasons for discontinuation or modifications of the first-line cART regimens have been investigated in a number of recent studies8–17 in which it has been underlined how discontinuation of initial therapy has decreased over time, but is still quite high even for the latest drug combinations.16 Data updated from the Italian Cohort

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of Antiretroviral-Naive Patients (ICONA) on 2008 highlighted a 1-year probability of first cART stopping of 36.1%; moreover, it has been noticed that the incidence of discontinuation because of intolerance/toxicity has declined over time, whereas simplification strategies have become more frequent in recent years.11 The latest advances in refinement of cART strategies, regarding both new drugs and fixed dose formulations, have led to reconsider and change current guidelines for first antiretroviral regimens in naive patients,18 as has already happened for multiple other drugs in the past years.19 Furthermore, evaluations of the prevalence and predictors of initial cART discontinuation have demonstrated that certain patients are more likely to discontinue treatment.20–22 For this reason, identifying groups at increased risk of cART discontinuation could support clinicians in the choice and optimization of first-line therapy for the individual patient. The aims of this analysis were (1) to estimate the frequency and causes of discontinuation of treatment regimens initiated in very recent years in HIV-infected patients seen for care in Italy and (2) to evaluate factors associated with treatment discontinuation.

virological or clinical); nonadherence; planned discontinuation (including structured treatment discontinuation, end of pregnancy, and medical decision); other causes (including patients decision, pregnancy, enrollment, or ending of a clinical trial and drug–drug interaction), as reported by the treating physician. Three main discontinuation endpoints have been considered: (1) because of toxicity, (2) intolerance, and (3) simplification. These have been decided a priori as likely to be the 3 main reasons for stopping drugs in the modern era of cART, as previously shown.11 Potential predictors of the risk of stopping, which have been examined separately for all 3 endpoints, included: sex, mode of HIV transmission, nationality (an immigrant patient was considered a patient born outside Italy), AIDS diagnosis, cardiovascular disease diagnosis, hepatitis B and C diagnosis, calendar year of baseline, age, lymphocyte T CD4+ and CD8+ cell count, HIV-RNA plasma level, diabetes, total cholesterol, and high-density lipoproteins cholesterol (categorical variable, above and below 40 mg/ dL for men and 50 mg/dL for women), use of statins, use of blood pressure lowering drugs, time from HIV diagnosis to date of starting cART, estimated glomerular filtration rate, blood glucose, third drug and backbone combined in the regimen, mental health disorders.

METHODS Patient Population

Statistical Analysis

ICONA Foundation Study (ICONA) is a multicenter prospective observational study of HIV-1–infected patients, which was set up in 1997. Eligible patients were those starting cART when they were naive to antiretrovirals, regardless of the reason for which they had never been treated and the stage of the disease. All patients signed consent forms to participate to the ICONA, in accordance with the ethical standards of the committee on human experimentation and the Helsinki Declaration (1983 revision). Demographic, clinical and laboratory data, and information on therapy are collected for all participants and recorded online www.icona.org. Patients who had initiated their initial cART regimen after January 1, 2008 and had at least 1 month of clinical follow-up were included in this analysis; follow-up lasts up to the end of October 2014. Discontinuation of the first regimen was defined as stopping and/or switching of at least 1 drug contained in the regimen; we had ignored all changes in formulations that did not imply a modification in the drug used [eg, changing from tenofovir/emtricitabine (TDF/FTC) plus efavirenz (EFV) to a single-tablet regimen (STR) containing TDF/FTC/EFV]. All causes of discontinuation were coded in the ICONA database, including simplification (defined either as the reduction of drugs included in the regimen or the decrease in daily doses or pills); intolerance defined as patient’s related lack of tolerance (eg, unwillingness or refusal to tolerate the prescribed drug in the absence of any clinical and laboratory signs of drug harmfulness); toxicity defined as a stop likely to be caused by adverse effects related to exposure to that drug. This includes drug-related side effects and adverse reactions, defined as the response to a drug, which is noxious and unintended and which occurs at normally used doses; failure (either

Standard survival analysis was used to estimate the time to treatment discontinuation (endpoints defined as above). Patients’ follow-up accrued from the date of starting their first cART regimen from ART-naive up to the date of discontinuation or last clinical visit. Kaplan–Meier (KM) curves were drawn using a marginal model approach such as follow-up of patients who discontinued for a reason different from that of interest was truncated at the date of last clinical follow-up (administrative censoring). Overall cumulative risk of stopping was estimated using the KM method and all curves stratified by reason fore stopping were plotted on the same graph. Cox regression analysis was used to identify factors associated with the risk of treatment discontinuation because of the 3 reasons described. We used a cause-specific hazard approach as our main analysis and the Fine–Gray approach as an alternative analysis with the objective of prediction (see Table S1, S2, S3, Supplemental Digital Content, http://links.lww.com/QAI/A754). All variables considered in the univariable model have been also included in the multivariable model.

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RESULTS We included in the study 4052 patients, satisfying the entry criteria. Men were 3197 (78.9%), mean age was 39 years (range: 32–47 years), 796 patients (19.6%) were 18–30 year old, 2562 (63.2%) were 31–50 years old and 694 (17.1%) were more than 50 old. In Table 1, demographic characteristics of patients included in the study are illustrated. The most frequently prescribed regimens and their prescriptive distribution over time are showed in Table 2. Globally, protease inhibitor (PI)–containing regimens accounted for the

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Discontinuation of First-Line Regimen in the Antiretroviral Era

TABLE 1. ART Discontinuation and Reasons in Late cART Era Discontinuation Characteristics Gender, n (%) Female Mode of transmission, n (%) Intravenous drug use Homosexual contacts Heterosexual contacts Other/unknown Nationality, n (%) Being immigrant AIDS diagnosis, n (%) Yes Calendar year of baseline Median (IQR) Age, years Median (IQR) CD4 count, cells/mmc Median (IQR) CD4 count nadir, cells/mmc Median (IQR) CD8 count, cells/mmc Median (IQR) Viral load, log10 copies/mL Median (IQR) Total cholesterol, mg/dL Median (IQR) HDL cholesterol, mg/dL Median (IQR) Use of statins, n (%) Yes Blood glucose, mg/dL Median (IQR) Antivirals started, n (%) Zidovudine Lamivudine Abacavir Tenofovir Emtricitabine Efavirenz Nevirapine Rilpivirine Liponavir/r Atazanavir/r Darunavir/r Raltegravir Age (yrs), n (%) 18–30 31–50 50+

Yes (N = 1389)

No (N = 2663)

318 (22.9)

537 (20.2)

P*

Total (N = 4052)

0.043 855 (21.1%) 0.166 103 569 617 95

(7.4) (41.1) (44.4) (6.9)

229 1068 1133 222

(8.6) (40.3) (42.5) (8.4)

332 1637 1750 317

(8.2) (40.6) (43.2) (7.9)

0.169 253 (18.2)

598 (22.5)

851 (21.0) 0.062

168 (12.1)

271 (10.2)

439 (10.8) ,0.001

2011 (2009, 2012)

2012 (2011, 2013)

2012 (2010, 2013) ,0.001

40 (33, 48)

39 (32, 47)

39 (32, 47) 0.007

297 (159, 400)

313 (185, 422)

308 (176, 413) 0.029

284 (155, 382)

300 (173, 394)

294 (166, 391) 0.683

655 (473, 820)

660 (474, 832)

659 (473, 826) 0.019

4.77 (4.13, 5.27)

4.68 (4.02, 5.21)

4.71 (4.05, 5.23) 0.266

160 (136, 184)

161 (137, 187)

161 (136, 186) 0.592

38 (31, 47)

38 (31, 47)

38 (31, 47) 0.054

26 (1.9)

30 (1.1)

56 (1.4) 0.838

86 (79, 94) 96 199 90 1192 1181 503 23 8 279 308 206 48

(6.9) (14.3) (6.5) (85.8) (85.0) (36.2) (1.7) (0.6) (20.1) (22.2) (14.8) (3.5)

86 (79, 94) 52 360 285 2310 2295 704 56 304 200 611 630 115

86 (79, 94)

(2.0) (13.5) (10.7) (86.7) (86.2) (26.4) (2.1) (11.4) (7.5) (22.9) (23.7) (4.3)

148 559 375 3502 3476 1207 79 312 479 919 836 163

(3.7) (13.8) (9.3) (86.4) (85.8) (29.8) (1.9) (7.7) (11.8) (22.7) (20.6) (4.0)

0.002 246 (17.7) 870 (62.6) 273 (19.7)

550 (20.7) 1692 (63.5) 421 (15.8)

796 (19.6) 2562 (63.2) 694 (17.1)

*Chi-square or Kruskal–Wallis test as appropriate. HDL, high-density lipoprotein; IQR, interquartile range; r, ritonavir.

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TABLE 2. Most Frequent Regimens and Their Prescriptive Distribution Over Time Regimens Frequency Abacavir/lamivudine +atazanavir/ritonavir

Abacavir/lamivudine +darunavir/ritonavir

Other

Tenofovir/emtricitabine +atazanavir/ritonavir

Tenofovir/emtricitabine +darunavir/ritonavir

Tenofovir/emtricitabine +lopinavir/ritonavir

Tenofovir/emtricitabine +raltegravir

Tenofovir/emtricitabine/ efavirenz

Ttenofovir/emtricitabine/ rilpivirine

Years 2008–2010 2011–2012 2013–2014 23 52 37

Total 112

0.57 20.54 1.95 9

1.28 46.43 3.15 52

0.91 33.04 3.02 51

2.76

0.22 8.04 0.76 172 4.24 36.29 14.61 220

1.28 46.43 3.15 196 4.84 41.35 11.87 385

1.26 45.54 4.17 106 2.62 22.36 8.66 177

2.76

5.43 28.13 18.69 94

9.50 49.23 23.32 341

4.37 22.63 14.46 256

19.30

2.32 13.60 7.99 230

8.42 49.35 20.65 69

6.32 37.05 20.92 44

17.05

5.68 67.06 19.54 27

1.70 20.12 4.18 41

1.09 12.83 3.59 58

8.46

0.67 21.43 2.29 402

1.01 32.54 2.48 512

1.43 46.03 4.74 203

3.11

9.92 35.99 34.15 0

12.64 45.84 31.01 3

5.01 18.17 16.58 292

27.57

0.00 0.00 0.00 1177 29.05

0.07 1.02 0.18 1651 40.75

7.21 98.98 23.86 1224 30.21

7.28

112

474 11.70

782

691

343

126

1117

and 145 (3.6%), the backbone was represented by abacavir/ lamivudine and zidovudine/lamivudine respectively. Over a median follow-up of 12 months, 1389 patients stopped their cART with an overall discontinuation rate of 34.3%. The likelihood of discontinuation by KM was 26% by 1 year [95% confidence interval (CI): 23.8 to 28.2], 39.7% by 2 years (95% CI: 37.0 to 42.4), and 48.5% by 3 years (95% CI: 45.4 to 51.6), as showed in Figure 1. Main reason for stopping at least 1 drug in regimen was simplification (29.1%), followed by intolerance (21.1%), toxicity (18.6%), other causes (17.8%), failure (8.2%), planned interruption (3.5%), and poor adherence (1.7%). Reasons for discontinuation by year since starting cART are illustrated in Figure 2. Three hundred seven patients (76%) simplified their regimens to STR as second-line cART [268 patients in TDF/FTC/EFV and 39 patients in TDF/FTC/rilpivirine (RPV)]. In a multivariable Cox model, independent predictors of discontinuation for the main reasons (simplification, intolerance, and toxicity) were analyzed (Table 3). Independent predictors associated with higher likelihood of simplification were heterosexual intercourse as risk factor for HIV transmission [hazard ratio (HR) 5.13; CI: 95% 1.57 to 16.74; P = 0.007] and a higher nadir lymphocyte T CD4+ cell (HR 1.72; CI: 95% 1.13 to 2.61; P = 0.011), whereas being immigrant (HR 0.39; CI: 95% 0.18 to 0.85; P = 0.017), higher pretreatment lymphocyte T CD8+ cell counts (HR 0.89; CI: 95% 0.81 to 0.99; P = 0.025) were associated with lower likelihood. For discontinuation due to intolerance, an association was found using statins (HR 2.99; CI: 95% 1.11 to 7.69; P = 0.029) and higher blood glucose levels (HR 2.11 CI: 95% 1.00 to 4.47). Independent predictors of discontinuation due to toxicity were higher blood glucose levels (HR 3.12; CI: 95% 1.31 to 7.41; P = 0.010) and the use of zidovudine/ lamivudine as backbone (HR 3.72 CI: 95%1.04 to 13.34; P = 0.044). Among available data (n = 3638) about virological status at 2 years after starting cART, 3597 patients (98.9%) achieved viral suppression with HIV-RNA, 50 copies per milliliter (see Figure S1, Supplemental Digital Content, http://links.lww.com/QAI/A754).

295

DISCUSSION

55.6% of the patients (n = 2252), non-nucleoside reverse transcriptase inhibitors–containing regimens were the firstline choice in 39.5% of the patients (n = 1601); in 199 patients (4.9%), integrase inhibitors and/or CCR5 inhibitors were the third drugs of combinations (raltegravir was used as part of 126 regimens). Looking at the NRTI backbone, in 3472 patients (85.7%), TDF/FTC was used; in 375 (9.2%)

In this analysis from the ICONA cohort, we offer new data for estimating the proportion of HIV-infected naive patients who discontinue their first-line cART and for identifying characteristics associated with treatment discontinuation in clinical practice. By our data, in the late of antiretroviral therapy era, the main reason for stopping the first-line treatment is simplification. These data suggest that there is an ongoing prescriptive trend, which leads to prioritize the regimen choice by simplifying the cART to enhance patient adherence, improve quality of life, minimize drug-related toxicity, and eventually provide a cost containment, because of an increase in the number of available drugs and regimen combination options and according to the changes in national and international recommendations.18,23

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Total

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Discontinuation of First-Line Regimen in the Antiretroviral Era

FIGURE 1. Overall Kaplan–Meier estimates of the risk of stopping.

In a previously reported analysis of the ICONA cohort conducted from January 2007 to June 200811 in the first year after cART initiation, the overall risk of discontinuation of initial therapy was 36% with 5.2% because of simplification. In this analysis, the simplification reaches 29%: the use of new drug combinations aimed to simplify dosing frequency and reduce pill burden as STR. In this cohort, it has been highlighted a great rate of simplification to STR (76.%). In fact, it has been suggested that the performance of patients who switched to an STR compared to patients remaining on a more complex regimen is better, both in terms of virological response and persistence.24–26 Furthermore, this high rate of simplifications may also reflect the increase frequency of

FIGURE 2. Kaplan–Meier estimates according to reason for stopping. STI, structured treatment interruptions. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

pro-active switches in virologically suppressed patients finalized to prevent long-term toxicity in a population that is expected to become older and have age-related comorbidities similarly to non-HIV–infected people.27 Moreover, the Italian economic crisis, with the contraction of the government budget, favors cheaper drugs and/or alternative treatment regimens, might have played a role in influencing the decision of clinicians on behalf of switches strategies.28 Indeed, in our country, STRs (TDF/FTC/EFV and TDF/ FTC/RPV) are cheaper than PI/r-based regimes and TDF/ FTC/EVG/cobicistat price is comparable to that of PI/r-based regimens. We were not referring to the comparison of the price of STR with that of its non-STR equivalent. In our cohort rate of treatment, discontinuation due to poor adherence was only 1.7% versus 24% in the previous ICONA analysis; these data reflect the improvements of drug formulation and regimen convenience, and the trend of clinicians in favor of individualization of cART. Moreover, the recent introduction of the fixed-dose, single-tablet formulation of TDF/FTC/RPV for the treatment of HIV-infected adults with a more favorable tolerability profile than TDF/FTC/ EFV have contributed in improving patient adherence.29–33 It is important to underline that at the time of this analysis TDF/FTC/elvitegravir/cobicistat and dolutegravir were not available in Italy, whereas the use of TDF/FTC/RPV was not available for the switch on the whole Italian peninsula. These data may support the auspice that in a next future, discontinuation rate due to low adherence and intolerance will decrease over time thanks to the second wave of STR (TDF/ FTC/elvitegravir/cobicistat, abacavir/lamivudine/dolutegravir) and the new formulations containing protease inhibitors (darunavir and atazanavir) plus cobicistat. Furthermore, because of evolving guidelines recommendations, more www.jaids.com |

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Di Biagio et al

TABLE 3. Independent Predictors of Discontinuation Due to Simplification, Intolerance, and Toxicity Relative Hazards of Discontinuation Due to Simplification Adjusted Relative Hazards (95% CI) Gender Female versus male Mode of HIV transmission Injection drug user Homosexual contacts

1.00 3.79 (1.16 to 12.34) 5.13 (1.57 to 16.74) 5.94 (1.47 to 24.08)

268

P

Global P

1.36 (0.70 to 2.65) 0.366

0.789

Adjusted Relative Hazards (95% CI)

P

1.10 (0.49 to 2.51)

0.813

1.00 0.60 (0.21 to 1.75)

0.352

1.00 0.94 (0.30 to 2.89) 0.910

0.007

1.14 (0.39 to 3.32) 0.809

0.37 (0.14 to 1.01)

0.053

0.013

1.39 (0.35 to 5.46) 0.637

0.42 (0.13 to 3.10)

0.247

0.39 (0.18 to 0.85) 0.017

1.05 (0.51 to 2.16) 0.897

0.98 (0.40 to 2.38)

0.958

1.76 (0.80 to 3.84) 0.159

0.27 (0.06 to 1.26) 0.097

1.37 (0.51 to 3.63)

0.531

1.83 (0.19 to 18.02)

0.604

1.00 1.14 (0.43 to 3.02) 1.21 (0.53 to 2.75)

0.787 0.655

5.81 (0.67 to 50.76)

0.009

Relative Hazards of Discontinuation Due to Toxicity

0.027

Other/unknown

Hepatitis coinfection,* n (%) No Yes Not tested Calendar year of baseline Per more recent year Age Per 10 yrs older CD4 count Per 100 cells/mm3 higher CD4 count nadir Per 100 cells/mm3 higher CD8 count Per 100 cells/mm3 higher HIV-RNA viral load Per log10 copies/mL higher Diabetes, n (%) Yes versus no Total cholesterol Per 100 mg/dL higher HDL cholesterol Altered versus normal Use of statins Yes versus no Use of blood pressure lowering drugs (%) Yes versus no

Adjusted Global Relative Hazards P (95% CI)

1.15 (0.72 to 1.19) 0.640

Heterosexual contacts

Nationality Being immigrant versus Italian AIDS diagnosis Yes versus no Cardiovascular disease Yes versus no

P

Relative Hazards of Discontinuation Due to Intolerance

0.112

1.00 1.57 (0.74 to 3.35) 0.244 0.78 (0.39 to 1.58) 0.490

0.962

1.00 1.00 (0.37 to 2.66) 0.997 1.68 (0.85 to 3.33) 0.134

0.470

0.790

0.90 (0.77 to 1.05) 0.186

0.98 (0.81 to 1.19) 0.856

1.27 (1.00 to 1.62)

0.054

0.91 (0.71 to 1.18) 0.498

1.07 (0.80 to 1.43) 0.644

1.02 (0.73 to 1.42)

0.924

0.75 (0.51 to 1.09) 0.136

1.00 (0.64 to 1.55) 0.986

0.62 (0.44 to 1.81)

0.751

1.72 (1.13 to 2.61) 0.011

1.16 (0.71 to 1.89) 0.546

0.96 (0.29 to 1.34)

0.259

0.89 (0.81 to 0.99) 0.025

1.06 (0.94 to 1.20) 0.339

0.99 (0.86 to 1.13)

0.847

0.94 (0.77 to 1.16) 0.587

1.25 (0.96 to 1.63) 0.102

0.82 (0.62 to 1.08)

0.161

0.977

0.59 (0.05 to 7.10) 0.674

1.46 (0.21 to 10.45)

0.704

1.22 (0.68 to 2.20) 0.504

0.56 (0.28 to 1.14) 0.199

0.99 (0.48 to 2.05)

0.976

1.08 (0.70 to 1.66) 0.723

1.41 (0.83 to 2.40) 0.029

0.52 (0.27 to 1.03)

0.060

1.30 (0.42 to 4.06) 0.651

1.41 (0.83 to 2.40) 0.199

0.94 (0.26 to 3.45)

0.926

0.69 (0.08 to 5.92) 0.731

1.36 (0.25 to 7.39) 0.029

2.12 (0.38 to 11.75)

0.391

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Global P

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J Acquir Immune Defic Syndr  Volume 71, Number 3, March 1, 2016

Discontinuation of First-Line Regimen in the Antiretroviral Era

TABLE 3. (Continued ) Independent Predictors of Discontinuation Due to Simplification, Intolerance, and Toxicity Relative Hazards of Discontinuation Due to Simplification Adjusted Relative Hazards (95% CI) Time from HIV diagnosis to date of starting cART Per year longer eGFR (CKD_Epi formula) Per 60 mL/min per 1.73 m higher Blood glucose Per 100 mg/dL higher NRTI started Tenofovir/ emtricitabine Zidovudine/lamivudine Abacavir/lamivudine Other NRTI pair Third drug started NNRTI (yes versus no)

P

Relative Hazards of Discontinuation Due to Intolerance

Adjusted Global Relative Hazards P (95% CI)

P

Global P

Relative Hazards of Discontinuation Due to Toxicity Adjusted Relative Hazards (95% CI)

P

1.02 (0.97 to 1.07) 0.449

0.98 (0.92 to 1.03) 0.421

0.98 (0.93 to 1.04)

0.496

0.56 (0.12 to 2.62) 0.462

0.82 (0.14 to 4.84) 0.823

0.63 (010 to 4.07)

0.623

0.66 (0.30 to 1.46) 0.304

2.11 (1.00 to 4.47) 0.050

3.12 (1.31 to 7.41)

0.010

,0.001

1.00 0.62 (0.14 to 2.74) 0.527 0.88 (0.41 to 1.87) 0.734 2.05 (0.28 to 0.478 15.04)

3.14 (0.15 to 65.49) PI or PI/r (yes versus 1.58 (0.08 to no) 32.02) Other class (yes versus 0.78 (0.05 to no) 12.02) Mental health disorders 0.23 (0.03 to 1.73) (yes versus no)

0.461 0.765 0.861

,0.001

1.00

,0.001

1.00

2.26 (0.80 to 6.39) 0.125 015 (0.02 to 1.09) 0.060 3.18 (0.79 to 0.104 12.82)

3.72 (1.04 to 13.34) 0.55 (0.16 to 1.87) 1.87 (0.11 to 32.21)

0.044 0.340 0.667

5.01 (0.47 to 0.180 52.76) 3.12 (0.30 to 0.338 32.05) 1.42 (0.22 to 9.05) 0.710

8.46 (0.51 to 141.8)

0.138

14.26 (0.83 to 245.5)

0.067

1.69 (0.11 to 27.16)

0.710

2.50 (0.65 to 9.54)

0.181

0.154

Global P

*HDL level: .40 mg/dL for men and .50 mg/dL for women. eGFR, estimated glomerular filtration rate; NRTI, nucleoside analog reverse transcriptase inhibitors; NNRTI, non-nucleoside analog reverse transcriptase inhibitors; r, ritonavir.

patients will start their first cART regimen directly with STR or with integrase inhibitor including regimens and it could be foreseen that the rate of switches due to simplification will dramatically decrease. A reduction of virological failure rate has been observed in our cohort (8.2% versus 10.6% of previous analysis): this could be due to the correct use of genotypic resistance test at baseline in clinical practice and also to more potent, more tolerated regimens. Looking at simplification issues, in this analysis, we found that being immigrants was correlated with a lower rate of simplification. Notably, immigrant patients represent a more vulnerable population: it has been already demonstrated that immigrants are more likely to have a delayed in access to HIV care and with concurrent advanced AIDS.34,35 Furthermore in HIV-infected immigrants, the rate of retention to care is lower36 and the rate of adherence to cART.37 For these reasons, Italian physicians might have used different patterns of prescription for this population (eg, using regimens with high barrier to resistance) and subsequently immigrants have reduced possibility to discuss treatment simplifications with their treating physician. A predictor of simplification in this cohort was a higher nadir of lymphocyte Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

T CD4+, indicating that antiretroviral simplification is primarily performed in safer conditions. In a study, the median lymphocyte CD4+ at switch to TDF/FTC/RPV was over 500/mmc and risk factors for discontinuations or virological failure were lymphocyte CD4+ cell count below 200/mmc at the time of switch.38 Another predictor of simplification is heterosexual contact as risk factor for HIV transmission. Similarly to immigrants, heterosexual HIVinfected subjects are more likely to be diagnosed late and present advanced disease,39 probably because of a lower perception of being at risk of HIV infection that may have led to delayed testing: simplification strategies are justified in this population that starts first-line cART with a more complex regimen because of the wide immunological impairment or owing to opportunistic infections. Discontinuation due to intolerance is more likely to be in patients with a concomitant use of statins indicating a preexisting alteration of lipid profile that can lead more frequently to cART switch to improve metabolic profile and reduce cardiovascular risk. The statins are more effective than other classes of lipid-lowering drugs at reducing low-density lipoproteins cholesterol; they reduce the risk of heart disease, stroke, diabetes, and death.40 When considering treatment www.jaids.com |

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Di Biagio et al

switches to improve tolerability, it is critical to consider the agent with less impact on lipid profile. As previously reported,12,41 individuals starting a zidovudine/lamivudine-based regimens were more likely to modify their treatment because of toxicity compared to those treated with TDF/FTC-based regimens. Switch from zidovudine was associated with significant improvements in hemoglobin level and neutrophil counts parameters.42 Also, switch from a thymidine analog to TDF leads to significant improvement in limb fat mass, metabolic parameters, and mitochondrial toxicity.43–46 The impressive number of patients (99%) who achieve HIV-RNA below ,50 copies per milliliter gives the magnitude of the success of cART in the ICONA cohort and in Italian population. In fact, despite the discontinuation of the first-line cART, almost all patients resume therapy and are able to obtain a virological success. Some limitations should be recognized when interpreting the results of our study: the heterogeneity of the collection of the data on the single reason for discontinuation in cases of concomitant reasons (although this bias has been partially corrected by close central monitoring of all data), the potential poor ascertainment of mental health disorders that might have introduced bias because of residual confounding, the low number of events of interest. Another limitation is that patients’ mental health disorders and depression are recorded in the ICONA database although likely to be underestimated, and for this reason, they are not included in the analysis of predictors of discontinuation. However, the strength of this study is the large sample size and the ability to represent the prescription trend including very recent years of enrollment. In conclusion, the choice of different initial antiretroviral regimens in ICONA confirmed that there are differences in prescription practices in different Italian sites, whereas in second-line regimen simplification to STR appeared the preferred choice. As observed in clinical studies, virological success, measured with HIV-RNA below 50 copies per milliliter, is well defined also in practice. A clear trend toward tailored cART was highlighted. Further research evaluating the impact of the introduction in clinical practice of integrase inhibitors is needed. REFERENCES 1. Gulick RM, Mellors JW, Havlir D, et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med. 1997;337: 734–739. 2. Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med. 1997;337:725–733. 3. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998;338: 853–860. 4. Ray M, Logan R, Sterne JA, et al. The effect of combined antiretroviral therapy on the overall mortality of HIV-infected individuals. AIDS. 2010; 24:123–137. 5. Li TS, Tubiana R, Katlama C, et al. Long-lasting recovery in CD4 T-cell function and viral-load reduction after highly active antiretroviral therapy in advanced HIV-1 disease. Lancet. 1998;351:1682–1686.

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28. Llibre JM, Cardona G, Santos JR, et al. Antiretroviral treatment switch strategies for lowering the costs of antiretroviral therapy in subjects with suppressed HIV-1 viremia in Spain. Clinicoecon Outcomes Res. 2013;5: 215–221. 29. Wainberg MA. Combination therapies, effectiveness, and adherence in patients with HIV infection: clinical utility of a single tablet of emtricitabine, rilpivirine, and tenofovir. HIV AIDS (Auckl). 2013;5: 41–49. 30. Palella FJ, Fisher M, Tebas P, et al. Simplification to rilpivirine/emtricitabine/tenofovir disoproxil fumarate from ritonavir-boosted protease inhibitor antiretroviral therapy in a randomized trial of HIV-RNAsuppressed patients. AIDS. 2014;28:335–344. 31. Gantner P, Reinhart S, Partisani M, et al. Switching to emtricitabine, tenofovir and rilpivirine as single tablet regimen in virologically suppressd HIV-1 infected patients: a cohort study. HIV Med. 2015;16: 132–136. 32. Mills AM, Cohen C, Dejesus E, et al. Efficacy and safety 48 weeks after switching from efavirenz to rilpivirine using emtricitabine/tenofovir disoproxil fumarate-based single-tablet regimens. HIV Clin Trials. 2013;14:216–223. 33. Bernardini C, Maggiolo F. Triple combination rilpivirine, emtricitabine, and tenofovir (Complera/Eviplera) in the treatment of HIV. Patient Prefer Adherence. 2013;7:531–542. 34. Sulis G, El Hamad I, Fabiani M, et al. Clinical and epidemiological features of HIV/AIDS infection among migrants at first access to healthcare services as compared to Italian patients in Italy: a retrospective multicentre study, 2000–2010. Infection. 2014;42:859–863. 35. Girardi E, Sabin CA, d’Arminio Monforte A. Late diagnosis of HIV infection: epidemiological features, consequences and strategies to encourage earlier testing. J Acquir Immune Defic Syndr. 2007;45 (suppl 1):S3–S8. 36. Thierfelder C, Weber R, Elzi L, et al. Participation, characteristics and retention rates of HIV-positive immigrants in the Swiss HIV Cohort Study. HIV Med. 2012;13:118–126. 37. Oh DL, Sarafian F, Silvestre A, et al. Evaluation of adherence and factors affecting adherence to combination antiretroviral therapy among white, hispanic and black men in the MACS Cohort. J Acquir Immune Defic Syndr. 2009;52:290–293. 38. Pinnetti C, Di Giambenedetto S, Maggiolo F, et al. Simplification to coformulated rilpivirine/emtricitabine/tenofovir in virologically suppressed patients: data from a multicenter cohort. J Int AIDS Soc. 2014;17(4 suppl 3):19812. 39. Borghi V, Girardi E, Bellelli S, et al. Late presenters in an HIV surveillance system in Italy during the period 1992-2006. J Acquir Immune Defic Syndr. 2008;49:282–286. 40. Funderburg NT, Jiang Y, Debanne SM, et al. Rosuvastatin reduces vascular inflammation and T-cell and monocyte activation in HIVinfected subjects on antiretroviral therapy. J Acquir Immune Defic Syndr. 2015;68:396–404. 41. Smit M, Smit C, Geerlings S, et al. Athena Observational Cohort newer regimens are associated with improved tolerability. Changes in first-line cART regimens and short-term clinical outcome between 1996 and 2010 in The Netherlands. PLoS One. 2013;30:e76071. 42. Lafaurie M, Collin F, Bentata M, et al. Switch from zidovudine- to nonzidovudine-containing regimens is associated with modes haematological improvement and no obvius clinical benefit: a substudy of the ANRS 099 Alize trial. J Antimicrob Chemother. 2008;62:1122–1129. 43. Curran A, Ribera E. From old to new nucleoside reverse transcriptase inhibitors: change in body fat composition, metabolic parameters and mithocondrial toxicity after the switch from thymidine analogs to tenofovir or abacavir. Expert Opin Drug Saf. 2011;10:389–406.

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44. Moyle GJ, Sabin CA, Carttledge J, et al. A randomized comparative trial of tenofovir DF or abacavir as replacement for a thymidine analogue in persons with lipoathrophy. J Acquir Immune Defic Syndr. 2006;20:2043– 2050. 45. Reust CE. Common adverse effects of antiretroviral therapy for HIV disease. Am Fam Physician. 2011;12:1443–1451. 46. Pozniak A, Gallant JE, DeJesus E, et al. Tenofovir disoproxil fumarate, emtricitabine, and efavirenz versus fixed-dose zidovudine/lamivudine and efavirenz in antiretroviral-naive patients: virologic, immunologic, and morphologic changes—a 96-week analysis. J Acquir Immune Defic Syndr. 2006;43:535–540.

APPENDIX 1. Icona Foundation Study Group Board of Directors M Moroni (Chair), M Andreoni, G Angarano, A Antinori, A d’Arminio Monforte, F Castelli, R Cauda, G Di Perri, M Galli, R Iardino, G Ippolito, A Lazzarin, CF Perno, F von Schloesser, P Viale.

Scientific Secretary A d’Arminio Monforte, A Antinori, A Castagna, F CeccheriniSilberstein, A Cozzi-Lepri, E Girardi, S Lo Caputo, C Mussini, M Puoti.

Steering Committee M Andreoni, A Ammassari, A Antinori, C Balotta, A Bandera, P Bonfanti, S Bonora, M Borderi, A Calcagno, L Calza, MR Capobianchi, A Castagna, F Ceccherini-Silberstein, A Cingolani, P Cinque, A Cozzi-Lepri, A d’Arminio Monforte, A De Luca, A Di Biagio, E Girardi, N Gianotti, A Gori, G Guaraldi, G Lapadula, M Lichtner, S Lo Caputo, G Madeddu, F Maggiolo, G Marchetti, S Marcotullio, L Monno, C Mussini, M Puoti, E Quiros Roldan, R Rossotti, S Rusconi, M Santoro, A Saracino, M Zaccarelli.

Statistical and Monitoring Team A Cozzi-Lepri, I Fanti, L Galli, P Lorenzini, A Rodano, M Shanyinde, A Tavelli.

Participating Physicians and Centers Italy: A Giacometti, A Costantini, S Mazzoccato (Ancona); G Angarano, L Monno, C Santoro (Bari); F Maggiolo, C Suardi (Bergamo); P Viale, E Vanino, G Verucchi (Bologna); F Castelli, E Quiros Roldan, C Minardi (Brescia); T Quirino, C Abeli (Busto Arsizio); PE Manconi, P Piano (Cagliari); J Vecchiet, K Falasca (Chieti); L Sighinolfi, D Segala (Ferrara); F Mazzotta, S Lo Caputo (Firenze); G Cassola, C Viscoli, A Alessandrini, R Piscopo, G Mazzarello (Genova); C Mastroianni, V Belvisi (Latina); P Bonfanti, I Caramma (Lecco); A Chiodera, AP Castelli (Macerata); M Galli, A Lazzarin, G Rizzardini, M Puoti, A d’Arminio Monforte, AL Ridolfo, R Piolini, A Castagna, S Salpietro, L Carenzi, MC Moioli, C Tincati, G. Marchetti (Milano); C Mussini, C Puzzolante (Modena); A Gori, G. Lapadula (Monza); N Abrescia, A Chirianni, G Borgia, MG Guida, M Gargiulo, I Gentile, R Orlando (Napoli); F Baldelli, D Francisci (Perugia); G Parruti, T Ursini (Pescara); G Magnani, MA Ursitti (Reggio Emilia); R Cauda, M. Andreoni, A Antinori, V Vullo, A. Cingolani, A d’Avino, L Gallo, E Nicastri, R Acinapura, M Capozzi, R Libertone, G Tebano, M Zaccarelli (Roma); F Viviani, L Sasset (Rovigo); MS Mura, G Madeddu (Sassari); A De Luca, B Rossetti (Siena); P Caramello, G Di Perri, GC Orofino, S Bonora, M Sciandra (Torino); M Bassetti, A Londero (Udine); G Pellizzer, V Manfrin (Vicenza).

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Discontinuation of Initial Antiretroviral Therapy in Clinical Practice: Moving Toward Individualized Therapy.

Study aim was to estimate the rate and identify predictors of discontinuation of first combination antiretroviral therapy (cART) in recent years...
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